INSIGHT'S mission is to develop strategies for the optimization of treatment -- antiretroviral therapies (ART), immunomodulatory therapies, and interventions to prevent andtreat complications of HIVand ART- inorder to prolong disease-free survival in a demographically, socio-economically, and geographically diverse population of individuals infected with HIV. The specific research emphasis will be "optimization of clinical management, including co-morbidities," and will be characterized by 1) Large randomized trials with morbidity and mortality outcomes, and where appropriate preceded by vanguard studies to refine design parameters; 2) Studies relevant to both resource-rich and resource-poor countries; 3) Studies directed at minimizing the adverse effects of long-term treatment while maximizing the benefits; 4) Studies emphasizing co-enrollment so that more than one major research question can be addressed in the cohorts under follow- up; 5) Mechanistic substudies as part of larger trials; 6) Carefully planned epidemiological analyses, including nested case-control studies that take advantage of a large cross-study database and associated specimen repository; and 7) Linkages with other networks to maximize efficiency and research productivity. INSIGHT will conduct 5 or 6 large trials at approximately 400 sites in 35 countries, implementing the plan in a cost-effective way with emphasis on important principles ~ randomization, clinically relevant interventions, excellent long-term follow-up, and centrally adjudicated clinical outcomes. Through a carefully developed organizational plan that distributes responsibilities for international and local data quality assurance, high- quality data sets will be assembled to address important clinical management questions. With experienced investigators, collaborations with other networks, and the guidance of consultants in specialized areas, substantial and timely contributions will be made to the scientific literature and medical practice guidelines. These contributions will advance the DAIDS mission to promote progress in treatment - the discovery and development of therapies for HIV infection and its complications. The INSIGHT Leadership application includes three components: 1) Coordinating and Research Operations Center (CORE), 2) Network Laboratory (NL), and 3) Statistical and Data Management Center (SDMC). All three components will be colocated at the Coordinating Centers for Biometric Research, Division of Biostatistics, School of Public Health, at the University of Minnesota.